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United States Patent |
6,232,280
|
Shah
,   et al.
|
May 15, 2001
|
Cleaning product with analyzable and stable surfactant
Abstract
A cleaning composition includes a detectable substance which is relatively
stable in the cleaning composition, for indicating whether the cleaning
composition has been thoroughly removed from a vessel following a cleaning
process. For pharmaceutical applications, the detectable substance is
preferably a low-foaming surfactant that is detectable by high performance
liquid chromatography at concentrations of around 10 ppm, or less. The
surfactant is thus detectable in the same analytical procedure as are
traces of pharmaceutical residues which have not been removed from the
vessel. The analytical procedure is used to develop a cleaning protocol
for future cleaning processes by determining the number of rinses needed
for reducing the surfactant, and hence the cleaning product, and also the
pharmaceutical residues, in the rinse water to predetermined acceptable
levels.
Inventors:
|
Shah; Sayed Sadiq (St. Louis, MO);
Kaiser; Herb J. (Pontoon Beach, IL);
Keller; Shahin (St. Louis, MO)
|
Assignee:
|
Steris Corporation (Mentor, OH)
|
Appl. No.:
|
310421 |
Filed:
|
May 12, 1999 |
Current U.S. Class: |
510/179; 510/161; 510/382; 510/390; 510/434; 510/435; 510/436; 510/467 |
Intern'l Class: |
C11D 003/48; C11D 001/28; C11D 001/34; C11D 009/50 |
Field of Search: |
510/161,179,382,390,434,435,436,467
|
References Cited
U.S. Patent Documents
4485028 | Nov., 1984 | King | 252/99.
|
5143562 | Sep., 1992 | Boulos | 148/247.
|
5858941 | Jan., 1999 | Oakes et al. | 510/179.
|
Other References
Formulation Science, vol. 1, Proceedings from Formulations Forum '97, pp.
246-247 (Association of Formulation Chemists 1997), No Month Given.
Harcros Organics Literature: T-MULZ.RTM. Phosphate Esters (Aug. 15, 2000).
DeForest website (www.deforest.net/htms/hydrotro.htm) (Aug. 15, 2000).
Dow Chemical Company website (www.ajtsc.com/dow.htm) (Aug. 15, 2000).
Material Safety Data/Fiche Signaletique: RHODAFAC BP-769; Rhone-Poulenc
Canada, Inc. Sep. 13, 1994.
T-MULZ Emulsifiers: T-MULZ 211; Harcros Organics (1995), No Month Given.
|
Primary Examiner: Gupta; Yogendra
Assistant Examiner: Mruk; Brian P.
Attorney, Agent or Firm: Fay, Sharpe, Fagan, Minnich & McKee, LLP
Claims
Having thus described the preferred embodiment, the invention is now
claimed to be:
1. A cleaning composition for cleaning a residue from a surface, the
composition comprising:
a detectable surfactant as a sole surfactant in the cleaning composition,
which is stable in the cleaning composition and which is detectable at a
concentration of about 10 ppm or less, the surfactant being selected from
the group consisting of phosphate esters, aryl sulfonates, and aryl
disulfonates; and
18-25% by weight of a strong alkali selected from the group consisting of
sodium hydroxide, potassium hydroxide, and combinations thereof.
2. The composition of claim 1, wherein the surfactant is a phosphate ester
of the general formula:
##STR4##
where X is RO(CH.sub.2 CH.sub.2 O).sub.n or OM,
M is an alkali metal,
R includes an alkyl or phenyl group, and
n is from 2 to 10.
3. The composition of claim 2, wherein the phosphate ester is selected from
the group consisting of poly (oxy-1,2-ethanediyl),
alpha-phenyl-omega-hydroxy phosphate, and polyethoxylated polyarylphenol
phosptate.
4. The composition of claim 1, wherein the surfactant is low foaming.
5. The composition of claim 1 further including at least one
anti-redeposition agent or chelating agent selected from the group
consisting of gluconates, citrates, EDTA and salts thereof, and carboxylic
acid-based polymers.
6. The composition of claim 5, wherein the chelating agent includes EDTA or
a salt thereof at a concentration of 1-10% by weight of the composition
and the anti-redeposition agent includes sodium gluconate at a
concentration of 1-10% by weight of the composition and a polyacrylic acid
at a concentration of 0.1-2.0% by weight of the composition.
7. A cleaning composition for cleaning a residue from a surface, the
composition comprising, in terms of weight percent:
TBL
an anti-redeposition agent 1-10;
a strong alkali [at least] 18-50;
a chelating agent 1.0-10.0;
a surfactant 0.2-5; and
water Q.S.;
or below for serving as an indicator of whether the cleaning product has
been removed from the surface as a sole surfactant in the cleaning
composition, the surfactant being selected from the group consisting of
phosphate esters, aryl sulfonates, and aryl disulfonates.
8. The cleaning composition of claim 7, wherein the composition includes,
in terms of weight percent:
TBL
sodium gluconate 3-8;
potassium hydroxide 18-25;
sodium EDTA 2-5;
polyacrylic acid 0.1-2;
an aromatic phosphate ester 0.2-1; and,
water Q.S.
9. The cleaning composition of claim 7, wherein the surfactant is
detectable by high performance liquid chromatography at a concentration of
about 1 ppm, or below.
Description
BACKGROUND OF THE INVENTION
The present invention relates to the cleaning arts. It finds particular
application in conjunction with the detection of residual cleaning
products remaining on pharmaceutical processing equipment after cleaning,
and will be described with particular reference thereto. It should be
appreciated, however, that the invention is also applicable to a variety
of cleaning applications where it is desirable to ensure that the cleaning
product has been thoroughly removed before reuse of the equipment.
Industries such as the pharmaceutical industry clean tanks and other
processing equipment with detergent-based cleaners to remove traces of the
products processed in the equipment. For pharmaceutical applications, in
particular, it is important to ensure that the cleaning process has
effectively removed drugs and cleaning product residues from the equipment
so that there will be no cross contamination from one batch of the product
to another and therefore no physiological impact. The Food and Drug
Administration requires that tests be conducted to validate the cleaning
process.
The level of residual cleaning product remaining on the equipment after
cleaning is commonly determined by a non-specific analytical method, such
as Total Organic Carbon (TOC) analysis. This approach is limited in that
it only offers information about the water-soluble carbon content of all
components in the residue and not about specific components in the
cleaning product.
Currently, High Performance Liquid Chromatography (HPLC) is the method of
choice for determining the level of residual pharmaceutical product on the
equipment. The HPLC decive is calibrate using a sample of one or more of
the drug additives processed in the pharmaceutical equipment. A sample of
residue extracted from a wall of the processing tank, or other part of the
equipment, is compared with the calibrated sample and the remaining level
of pharmaceutical residue determined.
The HPCL technique is a highly sensitive method of detecting specific
components in the residue. However, the detecting has not been used for
detecting traces of the cleaning product on the equipment. Most components
of cleaning products do not contain a detectable species, or chromophore,
which can be detected by the HPLC. Moreover conventional surfactants used
in the cleaning products tend to degrade over time due to the highly
alkaline or acidic pH of the cleaning product and thus are not capable of
acting as stable indicators for the cleaning product.
The present invention provides a new and improved cleaning composition and
method for detection of residual cleaning composition after cleaning which
overcomes the above-referenced problems and others.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, a method of
evaluating a surface for removal of a cleaning composition after a
cleaning process, the cleaning composition including a detectable
substance which is stable in the cleaning composition is provided. The
method includes rinsing the surface to produce a rinsate which contains
the detectable substance to provide an indication of whether the cleaning
composition has been removed from the surface to at least a maximum
acceptable level.
In accordance with another aspect of the present invention, a cleaning
composition for cleaning a residue from a surface is provide. The
composition includes a detectable substance which is stable in the
cleaning composition and which is detectable at a concentration of about
10 ppm or less.
In accordance with another aspect of the present invention, a cleaning
composition for cleaning a residue from a surface is provided. The
composition includes, in terms of weight percent:
an anti-redeposition agent 1-10;
a strong alkali 9-50;
a chelating agent 1.0-10.0;
a surfactant 0.2-5; and
water Q.S.
The surfactant is one which is detectable at a concentration of 10 ppm or
below for serving as an indicator of whether the cleaning product has been
removed from the surface.
In accordance with another aspect of the present invention, a method for
determining whether a piece of equipment has been rinsed sufficiently to
remove a process residue and a cleaning composition used in cleaning the
process residue from the equipment is provided. The method includes
spectroscopically analyzing a rinsate from the equipment at a first
selected wavelength to determine whether a preselected component of the
process residue is above a minimum preselected level and spectroscopically
analyzing the rinsate at a second selected wavelength to determine whether
a spectroscopically detectable substance in the cleaning composition is
above a minimum preselected level.
One advantage of the present invention is the provision of a cleaning
composition which includes a detectable component for assessing whether
the cleaning product has been thoroughly rinsed from the equipment being
cleaned.
Another advantage of the present invention is that the detectable component
may be detected by HPLC.
Yet another advantage of the present invention is that it enables residual
cleaning product to be detected by the same method as is conventionally
used for detecting pharmaceutical residues.
A further advantage of the present invention is the provision of a
surfactant for a cleaning product which is detectable at extremely low
levels and is stable at strong pH.
Still further advantages of the present invention will become apparent to
those of ordinary skill in the art upon reading and understanding the
following detailed description of the preferred embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention may take form in various components and arrangements of
components, and in various steps and arrangements of steps. The drawing is
only for purposes of illustrating a preferred embodiment and is not to be
construed as limiting the invention.
The FIGURE is a schematic diagram of a flowpath for testing pharmaceutical
equipment for residues according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A cleaning composition for removing pharmaceutical materials from
processing equipment includes a detectable substance, preferably a stable
surfactant, for evaluating the level of cleaning composition remaining on
the processing equipment after cleaning.
With reference to FIG. 1, a cleaning process includes cleaning a piece of
pharmaceutical equipment by contacting the equipment with the cleaning
composition to remove pharmaceutical residues and other contaminants from
surfaces of the equipment. The cleaning composition may be used neat,
without further dilution, but is preferably diluted with water, or other
solvents, to form a solution of the cleaning composition. The cleaning
step optionally includes spraying, or otherwise impacting surfaces of the
pharmaceutical equipment with the cleaning composition or diluted cleaning
solution to provide physical as well as chemical cleaning.
The surfaces are then rinsed a number of times with water, or other
suitable solvent to remove traces of the residue and the cleaning
composition from the equipment. A sample of the final rinse is analyzed by
an analytical method to determine whether the concentrations of the
detectable substance and specific components of the pharmaceutical residue
are below a predetermined, acceptable level. The concentration of the
detectable substance is used as an indicator of the level of the cleaning
composition in the rinsate and as an indication of whether the cleaning
fluid has been removed from the equipment. A concentration of the
detectable substance which is above the acceptable level indicates that
the rinsing process has not been satisfactory and that traces of the
cleaning product above an acceptable level are likely to remain on the
equipment. A concentration of the detectable substance which is at or
below the acceptable level indicates that the rinsing process has been
satisfactory and that traces of the cleaning product at or below an
acceptable level are likely to remain on the equipment.
If either the concentration of the detectable substance or the
concentration of the residue component in the rinsate is above the
acceptable level, the equipment is subjected to one or more additional
rinses and the final rinsate is retested. The procedure is continued until
acceptable levels of the detectable substance and pharmaceutical residue
component are measured. The equipment is then ready for processing
pharmaceutical products without the risk of contamination by the cleaning
composition or the components of the pharmaceutical residue.
The total number of rinses used to clean the equipment to the acceptable
levels is then recorded and may be used in future cleaning cycles which
use the same cleaning composition to remove the same pharmaceutical
residue.
The number of rinses needed for cleaning the equipment varies with the
pharmaceutical products and the cleaning composition used. Pharmaceutical
products include components of differing toxicity or adverse combination
effects when carried over in the equipment to a different product
formulation. Thus, the acceptable level of each component varies, and the
number of rinses needed to achieve a safe level may vary accordingly. Some
pharmaceutical components are more difficult to remove than others, which
also affects the number of rinsings. Components of the cleaning
compositions, particularly surfactants, adhere to the equipment to
differing extents and thus affect the number of rinses required to
thoroughly remove the cleaning product. For each combination of
pharmaceutical product manufactured and cleaning composition used to
remove it, therefore, there will be a preferred number of rinses to ensure
thorough cleaning. Once the number of rinses has been established for a
particular piece of processing equipment and a particular combination of
pharmaceutical product and cleaning composition, it can be used for future
cleaning cycles. The equipment is preferably recalibrated at intervals to
ensure that thorough cleaning continues to be achieved.
The detectable substance is preferably one which is readily detectable by
conventional methods used to detect components of pharmaceutical residues.
Since HPLC is the preferred method of detecting pharmaceutical components
at low levels, the detectable substance is preferably also detectable by
HPLC. HPLC uses a combination of chromatography for separating the rinsate
into components, and UV/visible spectroscopy at a fixed wavelength,
dependent on the component to be analyzed. The HPLC is thus set to detect
for signals at two (or more) wavelengths, one corresponding to a known
component of the pharmaceutical product or other chemical expected to be
left in the equipment after processing, and one corresponding to the
detectable substance.
While HPLC is a preferred method of analysis since it is able to detect
concentrations of 1%, or below, in the rinsate, other methods are also
contemplated for detecting the detectable substance, such as
electrochemical methods and fluorescence. In an electrochemical method, an
applied voltage would correspond to the oxidation or reduction potential
of a particular functional group of the detectable substance. The current
flowing at that voltage would then be used to determine the concentration.
In a fluorescence method, the detectable substance would contain a
fluorescing group, detectable by a spectroscopic technique. Simple
UV/visible spectroscopy could also be used (without the HPLC
chromatographic column).
The detectable substance thus contains a species, (termed a chromophore, in
the case of HPLC or other UV/visible detection method), which is
detectable at low levels by the method of analysis used. The FDA requires
that the cleaning composition be removed to a level of 10 ppm in the final
rinse, or lower. Accordingly, the detectable substance is preferably
detectable at around 10 ppm, or lower, more preferably at a level of
around 1 ppm or below.
The detectable substance should also be stable in the cleaning composition.
Cleaning compositions tend to be highly alkaline (around pH 10-14) or
highly acidic (around pH 1-2) and thus many substances which include
chromophores are hydrolyzed in the strong pH. Because of this, the
concentration in the cleaning composition tends to diminish over time and
thus the level of the detectable substance detected is not representative
of the concentration of the cleaning composition in the rinsate. For
example, a mixed amphocarboxylate surf actant with eight carbon chains was
found to be unstable in an alkaline cleaning product, decreasing in
concentration, due to hydrolysis, from 1.83% in the cleaning product at 6
days after manufacture to 0.82after 41 days and 0.09% after 141 days and
thus could not be considered a stable surfactant. Preferred detectable
substances are stable at strong pH, i.e., either high pH (pH 1-2) and/or
low pH (pH 10-14). Most preferably, the surfactants are stable at both
high and low pH and are stable at around pH 1 and at around pH 14.
By stable, it is meant that the surfactant does not appreciably degrade
(i.e., the detectable substance does not degrade and become undetectable)
over the expected storage lifetime of the cleaning composition. Storage
times of cleaning compositions (the time between manufacture and use) are
usually less than about three months, so the detectable substance should
be stable for about three months, or longer. Preferably, no more than
10-20%, and more preferably no more than 5% of the detectable substance
degrades in a period of three months. Conventional cleaning compositions
tend to be alkaline, and thus detectable substances which are stable at
high pH (pH 10-14, and more preferably up to pH 13-14) are particularly
preferred. Of course, such substances may be stable at both high and low
pH.
Preferably, the detectable substance is at least as difficult to remove
from the walls of the equipment as other components of the cleaning
composition. For this purpose, surfactants are considered to be suitable
detectable substances, because they tend to adhere to the walls, taking
several rinses to remove them. However, conventional surfactants generally
used in cleaning compositions do not have all of the properties desired in
a detectable substance, including stability and detectability at low
levels.
For pharmaceutical applications in particular, the detectable substance, in
the case of a surfactant, is low foaming. For other applications, such as
in washers, moderate, or even high foaming surfactants may not pose a
problem, or may be preferred. By low foaming, it is meant that the
surfactant generates an average foam height of about 40 mm, or less, on
shaking (after 0 minutes standing), more preferably, around 30 mm, or
less, in the temperature range of 25-60.degree. C. By moderate foaming, it
is meant that the surfactant generates an average foam height of about
40-70 mm. High foaming means a foam height of 70 mm and above. Foam height
is the height of foam standing above the top of the solution.
To make the foam height measurements, a surfactant formulation was
prepared, as follows.
Component %
surfactant 0.55 (active)
KOH 22.5
octyl betaine as needed to couple surfactant
into solution
water Q.S.
A 1.6 mL sample of the surfactant formulation was further diluted to a
volume of S0mL with deionized water in a 250 mL graduated shaker flask.
The flask was shaken for 1 minute and measurements of foam height were
taken at 0, 5, 10, and 15 minutes after the shaking was complete.
Measurements were made at 25.degree., 40.degree., and 60.degree. C.
Preferred detectable substances are surfactants which are both detectable
and stable at either high and/or low pH. Examples of stable surfactants
which are detectable at a low levels and stable include phosphate esters,
aryl sulfonates, and aryl disulfonates. Each of these surfactants includes
at least one stable functional group which is detectable at low levels.
Examples of suitable phosphate esters are aromatic phosphate esters of the
general formula:
##STR1##
where X is RO(CH.sub.2 CH.sub.2 O).sub.n or OM;
M is an alkali metal, such as Na or K;
R includes an alkyl or phenyl group and preferably includes from 8-18
carbon atoms; and
n=2-10, preferably over 6, with a preferred distribution of about 7-18
carbons, preferably 8-17 carbons.
These phosphate ester species are good anionic surfactants. They are stable
over an extended period of time (less than 5% reduction in concentration
detected over 3 months) and detectable at concentrations of well below 10
ppm, sometimes at around 1 ppm or below.
Preferred phosphate esters in which X is RO(CH.sub.2 CH.sub.2 O).sub.n
include: poly (oxy-1,2-ethanediyl), alpha-phenyl-omega-hydroxy phosphate
obtainable under the trade name Rhodafac BP-769, and polyethoxylated
polyarylphenol phosphate, obtainable under the trade name Soprophor 3D33,
both obtainable from Rhone-Poulenc. Another preferred phosphate ester is
obtainable under the trade name T-MULZ 211 from Harcross, and is similar
to Rhodafac BP-769. Rhodafac BP-769 and T-MULZ 211 were found to be
detectable at around 1 ppm, or below. The Rhodafac BP-769 and the T-MULZ
211 surfactant products are also low foaming, while the Soprophor 3D33 is
moderate foaming. In stability tests carried out over a three month
period, both Rhodafac BP-769 (at 1% by weight of the composition) and
T-MULZ 211 (at 0.5% and at 1% by weight of the composition) were found to
be stable in the composition with no appreciable change in the measured
concentration of the surfactant in the composition over that time (much
less than 5% drop in concentration).
Preferred aryl sulfonates include alkylnapthalene sulfonates of the general
formula:
##STR2##
which are obtainable from PETRO under the trade name Petro ULF. This
product is low foaming. Sulfonates of this type have good stability, but
the sulfonate chromophore detection limit tends to be higher than that of
the phosphate ester chromophore. However, concentrations of 2 ppm, and
below are readily detectable.
Preferred aryl disulfonates include diphenyl oxide disulfonates of the
general formula:
##STR3##
where R is a long chain olef in, preferably with 8-18 carbon atoms, more
preferably around 16 carbon atoms.
An example of a suitable disulfonate is a C16 .alpha. olef in-based
diphenyl oxide disulfonate, obtainable under the trade name Dowfax 8390
from Dow Chemicals. It has good stability and it is detectable at around
1%, however it is high foaming, and thus is less suited to some
pharmaceutical applications.
The cleaning composition can be acidic or alkaline. A suitable alkaline
formulation includes 9-50% by weight of a strong alkali, such as sodium or
potassium hydroxide. The composition also includes the detectable
substance and water. Potassium hydroxide at a concentration of 18-25% is
preferred, with a particularly preferred concentration of about 21% by
weight potassium hydroxide.
When the detectable substance is a surfactant, selected from the
surfactants described above, it is preferably present in the cleaning
composition at a concentration of from 0.2 to 5%, more preferably at a
concentration of 0.2-1%, and most preferably at around 0.5-1% by weight of
the cleaning composition.
The composition preferably also includes a chelating agent for chelating
with water hardness salts, such as salts of calcium and magnesium,
deposited on the equipment to be cleaned. Suitable chelating agents
include, but are not limited to, carboxylic acid-based polymers, such as
polyacrylic acid, and ethylenediaminetetraacetic acid (EDTA) or salts
thereof.
The chelating agent or agents may be present at a concentration of
1.0-10.0% by weight, more preferably from 2-6%. A preferred composition
includes 2-6%, more preferably about 3.8% by weight of Na-EDTA, and
0.1-3%, more preferably about 0.3% by weight of polyacrylic acid.
The composition may also include an anti-redeposition agent, which inhibits
redeposition of soil on the equipment. Suitable anti-redeposition agents
include gluconates, such as sodium gluconate, and citrate salts.
Polyacrylic acid also acts as an anti-redeposition agent. The
anti-redeposition agent is preferably at a concentration of 1-10%, more
preferably 3-8%, and most preferably about 5-6% by weight of the
composition. A particularly preferred composition includes polyacrylic
acid at a concentration of 0.1-3%, more preferably about 0.3% by weight,
and sodium gluconate at a concentration of 1-10%, more preferably about 5%
by weight of the composition.
A preferred alkaline cleaning composition includes:
Component % by weight
Strong Alkali 9-50
Detectable substance 0.2-5
Chelating agent 1-10
anti-redeposition agent 1-10
Water Q.S.
A more preferred alkaline composition includes: A yet more preferred
composition includes:
Component % by weight
Sodium or 18-25
Potassium Hydroxide
Chelating Agent 2-5
(such as Na-EDTA)
Anti-redeposition agent 3-8
(such as gluconates, citrates,
carboxylic acid-based
polymers)
Aromatic phosphate ester 0.5-1
Water Q.S.
One particularly preferred alkaline composition includes:
Component % by weight
Potassium Hydroxide 18-25
Sodium EDTA 2-5
Sodium gluconate 3-8
Polyacrylic acid 0.1-2
Aromatic phosphate ester 0.2-5
Water Q.S.
A more particularly preferred alkaline composition includes:
Component % by weight
Sodium gluconate 5
Potassium Hydroxide 21
Sodium EDTA 3.8
Polyacrylic acid 0.3
T-MULZ or Rhodafac 0.5
Water Q.S.
Acidic formulations may be analogously formed by replacing the alkali in
the formulation with a strong acid, such as phosphoric acid.
While in no ways wishing to limit the scope of the present invention, the
following example shows the foaming characteristics of various
surfactants.
EXAMPLE
Foaming Characteristics of Surfactants
Foam heights of various surfactants were measured according to the method
described above. Table 1 lists the % octyl betaine needed to couple the
surfactant and foam heights measured after 0, 5, 10, and 15 minutes at
temperatures of 25.degree., 40.degree., and 60.degree. C.
TABLE 1
Foam Heights of Surfactants
%
Octyl
Sur- be- Min- Classifi-
factant taine utes 25.degree. C. 40.degree. C. 60.degree. C. Average
cation
Dowfax 3.0 0 50 60 80 63 Moderate
8390 5 36 40 40 39 Foaming
10 34 38 30 34
15 32 34 18 28
Petro 6.0 0 36 24 34 31 Low
ULF 5 18 18 10 15 Foaming
10 18 14 8 13
15 16 10 6 11
Rhoda- 0.0 0 30 30 26 29 Low
fac 5 0 0 0 0 Foaming
BP-769 10 0 0 0 0
15 0 0 0 0
Sopro- 4.0 0 40 40 46 42 Moderate
phor 5 30 26 28 28 foaming
3D33 10 30 26 20 25
15 20 24 14 19
The invention has been described with reference to the preferred
embodiment. Obviously, modifications and alterations will occur to others
upon reading and understanding the preceding detailed description. It is
intended that the invention be construed as including all such
modifications and alterations insofar as they come within the scope of the
appended claims or the equivalents thereof.
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